Abstract/Project Summary Severe skeletal muscle trauma resulting from ischemic damage, nerve transection injuries, or volumetric defects is an intractable problem. Dysfunction and disability owing to the latter are an increasingly significant clinical burden. To address this challenge, this proposal seeks to develop biomaterial delivery systems that regulate the micro-environmental factors that harness the pro-regenerative functions of recruited blood monocytes to enhance volumetric muscle healing outcomes. In a pre-clinical model of volumetric muscle loss, we have shown that delivery of immune modulatory small molecules targeted to bioactive lipid receptors increases wound repair macrophages within the injury niche and enhances repair mechanisms such as angiogenesis, matrix deposition, and muscle fiber regrowth. The overall hypothesis for the proposed research is that local pharmacological targeting of sphingosine 1-phosphate (S1P) receptors uniquely recruits Ly6Clo monocytes directly from blood to the injury niche where they serve as biased progenitors of wound healing macrophages within injured muscle. Our specific aims are as follows: Aim 1: To characterize inflammatory infiltrate into the murine spinotrapezius volumetric muscle loss model and immune cell interactions with muscle satellite cells; Aim 2: To assess the impact of local delivery of S1P receptor targeted small molecules from polymer scaffolds on myeloid cell accumulation and behavior after skeletal muscle injury; Aim 3: To evaluate functional outcomes within a critical-sized volumetric defect in the murine quadriceps in response to local delivery of S1P receptor targeted small molecules. As the sequelae of muscle injuries increases at a disproportionate rate with advancing age, the burden of muscle injury on an aging domestic population will be increasingly severe. Thud, mechanisms surrounding the healing of volumetric muscle defects must be elucidated in order to advance translational therapeutics.